Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:47])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([N:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[CH:25][CH:26]=3)[N:21]([C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)[CH:20]=2)=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:8][N:9]([CH3:47])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([N:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[CH:25][CH:26]=3)[N:21]([C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)[CH:20]=2)=[CH:17][CH:18]=1
Reactant: CN(C)CCOc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCNCC4)ccc23)cc1
Reaction time: 15 h

Procedure:
Trifluoroacetic acid (0.2 mL) was added to a mixture solution of tert-butyl 4-(3-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate (4.1 mg, 7.6 μmol) in methylene chloride (0.2 mL) at room temperature. After stirring for 15 hours, the reaction solution was concentrated under reduced pressure. After adding ethyl acetate and saturated sodium bicarbonate aqueous solution, the mixture was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The target compound was obtained as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)[CH:16]=[C:11]2[C:10]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(Br)cc23)cc1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4cccs4)cc23)cc1
Yield: 100.1 %

Procedure:
5-Bromo-3-(4-methoxy-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (117, 100.0 mg, 0.23 mmol), thiophene-2-boronic acid (59 mg, 0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (20.0 mg, 0.017 mmol), potassium carbonate (80 mg, 0.58 mmol), tetrahydrofuran (15.0 mL) and water (5.0 mL) were combined under an atmosphere of nitrogen. The reaction mixture was refluxed overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel chromatography to give compound 118 (100 mg).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.O=[C:24]1[CH2:29][CH:28]([C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][NH:25]1>C1(C)C=CC=CC=1>[NH:25]1[CH2:26][CH2:27][CH:28]([C:30]([O:32][CH3:33])=[O:31])[CH2:29][C:24]1=[S:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)C1CCNC(=O)C1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCNC(=S)C1
Yield: 176.7 %

Procedure:
Add Lawesson's reagent (9.2 g, 22.7 mmol) to a solution of methyl 2-oxopiperidine-4-carboxylate (6.5 g, 41.4 mmol) in toluene (83 mL) and heat to reflux for 2 hours. Cool the solution and concentrate to dryness under reduced pressure. Purify the residue by flash chromatography on silica gel, eluting with ethyl acetate:dichloromethane (gradient 5-15%) to afford the title compound (6.95 g). 1H NMR (CDCl3) δ 1.97 (m, 1H), 2.17 (m, 1H), 2.78 (m, 1H), 3.03 (m, 1H), 3.24 (m, 1H), 3.39 (m, 1H), 3.49 (m, 1H), 3.72 (s, 3H), 8.48 (bs, 1H).
Reaction SMILES: C1COCC1.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Mg]Br.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].C1(C)C=CC=CC=1>CCCCCC>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: COc1ccccc1Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1ccc2ccccc2c1
Reaction time: 48 h
Yield: 96 %

Procedure:
Using a THF solution of 2-naphthylmagnesium bromide (1.47 mL, 1.02 M, 1.5 mmol), and 1-chloro-2-methoxybenzene (142.6 mg, 1.0 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 70° C. for 48 hours in the same manner as in Example 2. After performing silica gel column chromatography (toluene=10, 20 and 40% in hexane), the above compound was obtained as a white solid (0.224 g, yield=96%, purity=>99% (GC analysis)).
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[C:18](=[O:21])[O:19][CH2:20][C:16]=2[CH:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=C.[O:24]=[O+][O-].CSC>CO.CCOC(C)=O>[O:21]=[C:18]1[C:17]2[CH:22]=[CH:23][C:14]([CH2:13][CH2:12][N:4]([CH2:1][CH:2]=[O:24])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[CH:15][C:16]=2[CH2:20][O:19]1
Reactant: O=[O+][O-]
Reactant: C=CCN(CCc1ccc2c(c1)COC2=O)C(=O)OC(C)(C)C
Solvent: CO
Solvent: CSC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC=O)CCc1ccc2c(c1)COC2=O

Procedure:
To a solution of tert-butyl allyl[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]carbamate (0.58 g, 1.8 mmol) in MeOH (50 mL) was bubbled ozone until it turned blue. Nitrogen was bubbled through the solution to remove excess ozone, which was followed by addition of dimethyl sulfide (1.4 mL, 18 mmol). The solution was allowed to warm up slowly. The mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated to afford the product. The crude material was used directly in the next step without further purification.
Reaction SMILES: C([N:3](CC)CC)C.CS(Cl)(=O)=O.[CH2:13]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][CH:21]([NH2:3])[CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCN(CC)CC
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: NC(COCCOCCOCCOCCOCCO)OCc1ccccc1
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
Triethylamine (1.45 mL, 10.74 mmol) and methanesulfonyl chloride (0.48 mL, 5.9 mmol) were added to a solution of hexaethyleneglycol monobenzyl ether (2.0 g, 5.37 mmol) in methylene chloride (30 mL) at 0° C. and the solution was stirred for 30 min at ice bath temperature. The reaction mixture was filtered and concentrated to an oil which was dissolved in 30% ammonium hydroxide solution (50 mL). The reaction mixture was heated at reflux for 3 days and concentrated. Residual water was removed by evaporation from toluene and the crude material was slurried with THF and filtered. The filtrate was concentrated at reduced pressure to provide the title compound as an amber oil (1.14 g, 57% yield). 1H-NMR (300 MHz DMSO-d6) δ: 7.77 (br s, 2H), 7.40-7.10 (m, 5H), 4.48 (s, 2H), 3.61-3.48 (m, 24H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:6]([C:7](=[O:16])[NH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:9]1[NH:8][C:7](=[O:16])[C:6]2[C:11](=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]c(=O)[nH]c2c1OC
Product: COc1ccc2c(=O)[nH]c(Cl)nc2c1OC

Procedure:
Equimolar amounts (0.10 mole) of 7,8-dimethoxy-2,4-(1H,3H)-quinazolinedione and phosphorous oxychloride are stirred at room temperature overnight and the volatiles evaporated in vacuo to afford a residue of 2-chloro-7,8-dimethoxy-4-(3H)-quinazolineone which is purified by washing with aqueous sodium bicarbonate, extraction with chloroform and evaporation of solvent. To the residue is added a solution of 0.10 mole of 3-methylpiperidine in 300 ml. of isoamyl alcohol and the mixture heated at reflux for three hours, the solvent is then evaporated in vacuo to afford 2-(3-methylpiperidin-1-yl)-7,8-dimethoxy-4(3H)-quinazolineone hydrochloride. To this is added 150 ml. of phosphorous oxychloride and the resulting mixture is heated at reflux for two hours. The liquids are evaporated to give a residue of 2-(3-methylpiperidin-1-yl)-4-chloro-7,8-dimethoxyquinazoline hydrochloride. The product is dissolved in dilute aqueous sodium bicarbonate, extracted with chloroform, dried (Na2SO4) and the solvent evaporated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12][Br:13])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(Br)nc1CBr
Yield: 98.8 %

Procedure:
2-Bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (17 g, 68.0 mmol, purchased from Ryan Scientific), N-bromosuccinimide (12.7 g, 71.4 mmol), and benzoyl peroxide (1.65 g, 6.8 mmol) were suspended in 222 mL of benzene and heated at reflux temperature for 16 h. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was washed successively with saturated bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic solvent was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-20% ethyl acetate in hexanes to produce 22.1 g of a light yellow solid. 1H NMR (CDCl3, 200 MHz): δ=4.88 (s, 2H), 4.37 (q, 2H, J=7.0 Hz), and 1.39 (t, 3H, J=7.0 Hz).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].C([O:15][C:16]([C:18]1[N:19]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)C.[OH-].[Na+]>C1COCC1>[OH:15][CH2:16][C:18]1[N:19]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:29])=[O:28])[C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(CO)cc3ccccc32)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To stirred solution of Red-Al (sodium dihydro-bis(2-methoxyethoxy)aluminate ≈70% in toluene) (30 mL) in dry THF (100 mL) cooled at 5° C. and under nitrogen was added dropwise and at this temperature a solution of compound of step 1 (26,8 g, 78 mmol) in dry THF (75 mL). After stirring one hour at 5° C. and then one hour at room temperature the mixture was cooled at 10° C. and treated dropwise with 2N NaOH, to effect hydrolysis of the intermediate complex. The organic phase was separated and the solvent in vacuo evaporated. The residue was solved in ethyl ether, the solution washed with water, dried over MgSO4 and evaporated to give the required alcohol (23.3 g, 98%) as a yellow oil; IR (film) 3500, 1597 cm-1.
Reaction SMILES: Br[C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[C:4]([CH3:16])[C:3]=1[OH:17].C[O-].[Na+].[C:21](OCC)(=[O:23])C.O>CO>[CH3:21][O:23][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[C:4]([CH3:16])[C:3]=1[OH:17]
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(c(Br)c1O)C(C)(C)CCC2(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(O)c(C)cc2c1C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 89.57 %

Procedure:
To the solution of 1-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (12.8 g, 43.06 mmol) and sodium methoxide in methanol (5.0M) was added CuBr (1.24 g, 8.61 mmol) followed by ethyl acetate (2.5 mL). The reaction was stirred and heated to reflux for 16 hours. The reaction mixture was cooled to room temperature then poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated to yield 1-Methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (9.58 g, 89.57%). 1H NMR (CDCl3): δ 1.27 (s, 6H), 1.36 (s, 6H), 1.63-1.67 (m, 4H), 2.21 (s, 3H), 2.53 (s, 3H), 2.57 (s, 3H), 3.87 (s, 3H), 3.90 (s, 3H), 5.15 (d, 1H), 6.30 (s, 1H), 6.94 (s, 1H), 6.98 (s, 1H), 7.13 (d, 1H), 8.35 (s, 1H). APCI-MS m/z 532 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[F:9].[N+]([C:13]1[CH:18]=CC=C[CH:14]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:9])[N:8]=[CH:18][CH:13]=[CH:14]2
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Nc1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: Fc1cc2ncccc2cc1Br

Procedure:
A mixture of 4-bromo-3-fluoro-phenylamine (2.85 g, 15 m mole), ferrous sulfate (0.95 g), glycerol (5.658 g, 4.5 ml), nitrobenzene (1.125 g, 0.93 ml) and concentrated sulfuric acid (2.61 mL) were heated gently. After the first vigorous reaction, the mixture was heated to reflux for 7 hours. Nitrobenzene was evaporated in vacuo. The aqueous solution was acidified with glacial acetic acid and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate=8/1) to return compound title as white crystals (1.44 g, 42.5%).
Reaction SMILES: C[O-].[Na+].C1(C)C=CC=CC=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]#[N:20].Cl.[C:22](=O)([O:25]C)[O:23][CH3:24]>O>[C:19]([CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])[C:22]([O:23][CH3:24])=[O:25])#[N:20]
Reactant: COC(=O)OC
Reactant: N#CCc1ccccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(C#N)c1ccccc1F
Temperature: 75 °C
Yield: 97.1 %

Procedure:
Sodium methoxide (51.84 g) was added to dry toluene (815 mL) in a 1 L reactor under a nitrogen atmosphere. The reaction mixture was heated to 75° C., and then a mixture of 2-fluorobenzeneacetonitrile (100 g) in dimethyl carbonate (131.64 g) was added at 70-74° C. over a period of 45 minutes. The reaction mixture was further maintained at this temperature (70-75° C.) for an additional 4.5 hours. The reaction mixture was then cooled to 25-30° C. and added to a mixture of HCl (110 g, 35.2 wt %) diluted with water (300 mL) at 10-15° C. using an addition funnel. The resulting layers were separated, and the aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (2×200 mL), dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound as a brown oily liquid (138.8 g, 94.8% yield).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(O)c1ccc(-c2ccc(F)cc2)nc1

Procedure:
Operations similar to those of Production Example 14 were conducted using 6-chloronicotinic acid and 4-fluorophenylboronic acid, to provide the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:32])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:5]([N:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6].[C:33](N1C=CN=C1)(N1C=CN=C1)=[S:34]>C1COCC1.ClCCl.O>[CH2:12]([N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:4]1[CH:16]=[CH:17][C:18]2[N:19]([CH2:20][CH2:21][CH2:22][N:23]([CH3:32])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:33](=[S:34])[NH:1][C:2]=2[CH:3]=1)=[O:6])[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)CCc2ccccn2)c(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)CN(CC(C)C)C(=O)c1ccc2c(c1)[nH]c(=S)n2CCCN(C)CCc1ccccn1
Temperature: 20 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
A mixture of 3-amino-N,N-diisobutyl-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino) benzamide (1.52 g, 1 eq) and thiocarbonyldiimidazole (0.74 g, 1.2 eq) in THF (30 ml) is stirred at approximately 20° C. for 15 hours. After concentration under reduced pressure at 40° C., the residue obtained is taken up in dichloromethane (80 ml) and water (30 ml). After decanting and extracting, the combined organic phases are washed with salt water, dried over Na2SO4 then evaporated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 8:2) produces the expected compound in the form of a light beige foam (1.2 g; 72% yield).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:44][S:45](Cl)(=[O:47])=[O:46].CCOC(C)=O>C(Cl)Cl.O>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:22][CH2:21]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:5]=2[N:4]=1
Reactant: CN(C)CCCOc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)CCCOc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 0 °C
Yield: 58.9 %

Procedure:
A stirred mixture of 297 mg (0.57 mmol) of N-[3-({2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine and 1 g of powdered K2CO3 in CH2Cl2 was cooled to 0° C. and 0.4 g of methanesulphonyl chloride was added. The mixture was allowed to warm to room temperature, and after 2 hrs it was diluted with water and the organic layer was separated and dried. Chromatography on alumina, eluting first with CH2Cl2/EtOAc (1:1) and then with EtOAc gave 200 mg (59% yield) of N-[3-({2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine: 1H NMR (CDCl3) δ 7.84 (dd, J=8.4. 0.6 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 4.32 (t, J=6.8 Hz, 2H), 4.02 (m, 4H), 3.88 (m, 4H), 3.78 (m, 4H), 3.33 (m, 4H), 2.81 (s, 3H), 2.54 (t, J=7.2 Hz, 2H), 2.28 (s, 6H), 2.14 (pentet, J=7.0 Hz, 2H); Hydrochloride: mp (EtOH) 243-247° C.; Anal. Calcd. for C25H36ClF2N9O4S.1.5H2O: C, 45.6; H, 6.0; Cl, 5.4, N, 19.1. Found: C, 45.5; H, 6.1; Cl, 5.2; N, 19.2%.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][N:21]([CH3:26])[C:22](=[O:25])[CH2:23][CH3:24])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][N:21]([CH3:26])[C:22](=[O:25])[CH2:23][CH3:24])=[O:19]
Reactant: [H][H]
Reactant: CCC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 77.2 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-N′-methyl-7-oxo-N′-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 226 (0.19 g, 0.52 mml) in methanol (20 mL) was added 5% Pd/C (0.20 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered through Celite, and the filtrate was evaporated to give (2R,5S)-6-hydroxy-N′-methyl-7-oxo-N′-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 227 (0.11 g, 79%) as a brown foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[C:27]([F:28])=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=1[F:29])[C:13](=[O:30])[CH:12]=[CH:11]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[N:46]=[C:47]([NH2:49])[CH3:48]>CN1C(=O)CCC1>[F:29][C:20]1[CH:21]=[C:22]([C:23]2[O:25][N:49]=[C:47]([CH3:48])[N:46]=2)[CH:26]=[C:27]([F:28])[C:19]=1[C:14]1[C:13](=[O:30])[CH:12]=[CH:11][N:10]2[C:15]=1[CH:16]=[CH:17][CH:18]=[C:9]2[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: O=C(O)c1cc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c(F)c1
Reactant: CC(N)=NO
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: ClCCCl
Product: Cc1noc(-c2cc(F)c(-c3c(=O)ccn4c(-c5ccc(F)cc5F)cccc34)c(F)c2)n1
Temperature: 90 °C

Procedure:
A solution of 4-[6-(2,4-difluorophenyl)-2-oxo-2H-quinolizin-1-yl]-3,5-difluorobenzoic acid (Example 38, 50 mg, 0.12 mmol) in NMP (1.2 mL) was added EDC (46 mg, 0.24 mmol), and HOBT (24 mg, 0.18 mmol) at room temperature. The reaction was stirred at room temperature for 30 minutes before N′-hydroxyethanimidamide was added. The reaction was heated to 90° C. for 6 hours and yielded an 80% conversion of product via LCMS. The reaction was quenched with NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with 0.5 N HCl, water, brine, dried over MgSO4, and concentrated. The residue was purified via silica gel chromatography (100% EtOAc) to give the title compound (9 mg).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[C:13]([Li])([CH3:16])(C)[CH3:14].[CH2:18]([Si:21](Cl)(C)[CH3:22])C=C.[NH4+].[Cl-]>C1COCC1>[CH2:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][C:3]=1[SiH:21]([CH3:22])[CH3:18])[CH:13]=[CH2:16]
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: C=CC[Si](C)(C)Cl
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCc1c([SiH](C)C)cc(Br)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution 1,4-dibromonaphthalene (28.6 g, 0.1 mol) in dry THF (800 mL) at −78° C. was added t-butyllithium (59.0 mL, 1.7 M solution in pentane, 0.1 mol) over a period of 20 min. After 30 min stirring at −78° C., allylchlorodimethylsilane (13.5 g, 0.1 mol) in THF (25 mL) was added dropwise over a period of 30 min. The reaction mixture was stirred further for 1 h and warmed to room temperature. Concentrated NH4Cl (5 mL) was added to the solution, and the reaction mixture was concentrated. The resulting yellow oil was concentrated, extracted with ethyl acetate/water, and the organic layer was dried, concentrated. The crude product was Kugelrohr distilled to give a colorless oil (25.6 g, 84%); 1H NMR (300 MHz, CDCl3) δ 0.57 (s, 6 H), 2.07 (d, J=8.10 Hz, 2 H), 4.94-5.04 (2 H), 5.87 (ddt, J=16.80, 10.20, 8.10 Hz, 1 H), 7.56 (d, J=7.20 Hz, 1 H), 7.61-7.70 (2 H), 7.83 (d, J=7.20 Hz, 1 H), 8.19 (m, 1 H), 8.43 (m, 1 H); 13C NMR (75 MHz, CDCl3) −1.5 (2 C), 24.5, 114.3, 126.0, 126.9, 127.1, 128.6, 128.8, 129.7, 132.2, 134.2, 134.7.